HIV
HIV is a lentivirus, which are members of the retrovirus family. HIV shows poor fidelity in replication (lipsky) this allows rapid mutation of the virual genome, and rapid resistance to develop to particular drugs Retroviriadae, whose genome is encoded in RNA. HIV has the gag/pol/env gene organization typical of other retroviruses. Reverse transcriptase (RT), an enzyme unique to retroviruses HIV contains two identical strands of +ssRNA within its capsid, along with the viral enzymes reverse transcriptase and integrase, p6, p7 and p24 HIV infection leads to low levels of CD4+ T cells through three main mechanisms: First, direct viral killing of infected cells; second, increased rates of apoptosis in infected cells; and third, killing of infected CD4+ T cells by CD8 cytotoxic lymphocytes that recognize infected cells. When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections.http://en.wikipedia.org/wiki/HIV of the nine HIV genes detection How do HIV tests work? The most commonly used HIV tests detect HIV antibodies – the substances the body creates in response to becoming infected with HIV. There are tests that look for HIV's genetic material or proteins directly; these may also be used to find out if someone has been infected with HIV. It can take some time for the immune system to produce enough antibodies for the antibody test to detect, and this “window period” between infection with HIV and the ability to detect it with antibody tests can vary from person to person. During this time, HIV viral load and the likelihood of transmitting the virus to sex or needle-sharing partners may be very high. Most people will http://www.cdc.gov/hiv/topics/basic/ subtypes HIV-1 and HIV-2 Two types of HIV have been characterized: HIV-1 and HIV-2. HIV-1 is the virus that was initially discovered and termed both LAV and HTLV-III. It is more virulent, more infective,8 and is the cause of the majority of HIV infections globally. The lower infectivity of HIV-2 compared to HIV-1 implies that fewer of those exposed to HIV-2 will be infected per exposure. Because of its relatively poor capacity for transmission, HIV-2 is largely confined to West Africa.9 structure the HIV virus contains 2 strands of +ssRNA within its capsid the viral enzyme reverse transcriptase the viral enzyme integrase protein p6 protein p7 the capsid is composed of the protein p24 the capsid is surrounded by the matrix protein p17 Lifecycle HIV life cycle has 10 steps video of the lifecycle part including reverse transcriptase; http://www.youtube.com/watch?v=eS1GODinO8w # adsorption # fusion # uncoating # reverse transcription # integration # replication # transcription # translation # budding # maturation Targets targets for antiviral action # prevent attachment of the virus to the cell # inhibition of reverse transcriptase # inhibition of rnase H, which degrades viral RNA after viral DNA has been synthesized # inhibition of viral integrase # inhibition of expression of the HIV geene # inhibition of processing and post-translational modification of protein products of the virus Compounds inhibiting HIV integrase, the third enzyme of HIV, REVERSE TRANSCRIPTASE INHIBITORS (RTIs) Nucleoside RTIs (NRTIs) and Nucleotide RTIs (NtRTIs) classes of treatments nucleoside analogues Proteinase inhibitors (PIS) if the proteins are not cleaved, then HIV is non-infectious saquinavir (first) followed by ritonavir indinavir. HIV protease inhibitors were based on a priori knowledge of the 3-D structure of the protein and its active site. S807 INTEGRASE Inhibitors (IN) Many such derivatives proved to belong to different classes of sulfonamides. Thus, investigation of the antibacterial sulfanilamide derivatives used clinically (such as sulfa- methoxazole, sulfadiazine, sulfathiazole, sulfadimethoxine, sulfisoxazole, etc.) for their interaction with IN, lead to the observation that sulfisoxazole and sulfasalazine were the most potent IN inhibitors, It is hoped that sooner or later an IN inhibitor should be available clinically in order to become a component of HAART regimens. Intervening on all three enzymes of HIV may lead to more durable viral suppression and possibly less toxic effects of the therapy. (Barbaro 2005) Non-nucleoside reverse-transcriptase inhibitors new developments ZINC NUCLEOCAPSIDE EJECTING AGENTS the final result is the denaturation of the zinc finger protein, which is lethal for the virus, leading to the formation of non- infective virions Viral Fusion (gp41) Inhibitors TARGETING HIV ENTRY INTO THE CELL HIV entry into the cell involves a number of steps which are potential targets for therapy. other S807 because the biochemistry of hepatitis B virus is related to that of HIV, in that both possess a reverse transcriptase, compounds originally developed for HIV are proving promising for treating HBV infections Barbaro tenofovir is one of the new NtRTIs which shows appreciable activity against many of the HIV strains resistant to the first generation NRTIs Lipsky HIV infection becomes more complex, care givers will require greater skill. = Eradication = There are various potential hiding places for the virus. Infectious viral particles have been isolated from follicular dendritic cells of peripheral lymphoid tissues. An important potential haven is infected macrophages; they cannot be killed by the virus, and are able to release virus continuously. The cen- tral nervous system and the testes may be reservoirs that create problems for drug penetration. However, the most important reservoir of HIV-1 is the resting memory CD4‡ T-cells carrying an inte- grated copy of the viral genome. They cannot be eliminated by the immune system because they do not have surface viral antigens, and the integrated viral genetic material cannot be targeted by current therapies A.G. Tomasselli, R.L. Heinrikson / Biochimica et Biophysica Acta 1477 (2000) 189^214